Project Summary/Abstract White matter ischemia is a progressive vascular disease that leads to focal neurological deficits, accumulates to cause dementia, and accelerates the pathology of Alzheimer's Disease. The term white matter ischemia or white matter hyperintensity, based on imaging, corresponds to several disease pathologies, including progressive blood brain barrier breakdown, small focal strokes and end-arterial hypoperfusion. White matter ischemia is strongly age-associated: at age 80 all of us will have white matter hyperintensities on MRI. Despite substantial pre-clinical study of mechanisms of white matter repair in inflammatory white matter disease (such as multiple sclerosis), there is little information on how cerebral white matter responds to white matter ischemia, and may initiate neural repair. This grant utilizes a model of white matter ischemia in the mouse, which produces diffuse and progressive damage from the small vessels in the subcortical white matter, to determine the mechanisms of white matter repair. The studies characterize candidate molecular systems that mediate this process and identify neuronal network function in white matter ischemia and during repair and recovery. The studies will determine the effects of age on these processes. This grant will use an innovative platform of technologies, including a newly developed mouse model, transgenic cellular fate-mapping, optogenetic and resting state MRI studies, and viral gain and loss of function approaches. The outcome of this work will be to identify novel molecular targets for neural repair in white matter ischemia, develop an understanding of the neuronal network function that leads to behavioral deficits in this disease, and develop an imaging biomarker for repair and recovery in white matter ischemia.